Avaliação de complexos proteína-ligantes e docking molecular na busca por anticoagulantes cumarínicos inibidores do fator X da coagulação sanguínea
Carregando...
Data
2010-10-28
Autores
Oliveira, Eliane Mari de
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
O objetivo deste trabalho foi o de buscar inibidores para o Fator X, fator comum da cascata de coagulação sanguínea. O primeiro passo para isso foi o de buscar conhecimento nos complexos cristalográficos entre o Fator X e pequenas moléculas. Após extensiva análise dos complexos obtidos de bancos de dados, onde foram avaliadas as interações e o posicionamento dos ligantes cristalográficos utilizando para isso a visualização molecular, os dados foram organizados e a informação transformada em conhecimento, principalmente sobre regiões de ocupação dos ligantes dentro do sítio ativo da serino-protease Fator X e a relação entre as atividades inibitórias extraídas da literatura. Em seguida foi estudada uma família de compostos cumarínicos onde a informação disponível era a das atividades dos compostos, e a formação de complexos foi realizada com estudos de docking e de visualização gráfica. Baseados no fato de que um dos anticoagulantes em uso é a varfarina, uma cumarina, que apresenta vantagens em alguns aspectos de sua utilização, como baixo custo e alta solubilidade, e desvantagens por sua ação não especifica, optou-se por estudar análogos da cumarina como inibidores do Fator X. Na terceira parte do trabalho, foram estudados complexos cumarínicos para os quais não se possuia conhecimento prévio sobre os complexos com o Fator X, nem dados de atividade inibitória. Os resultados da formação de complexos do Fator X e os análogos da cumarina obtidos com estudos de docking foram analisados com base nos conhecimentos adquiridos na primeira e segunda partes deste trabalho; isto levou à possibilidade de sugerir um composto que se encaixa nas características de um bom inibidor do Fator X.
The main aim of this work was to seek inhibitors of Factor X, the common factor of the cascade of blood coagulation. The first step was to gain enough insight in the understanding of the crystallographic complexes between the X-factor and small molecules. After extensive analysis of the complexes obtained from databases, using molecular visualization, data, namely the interactions of the ligands and their crystallographic pose, were organized and the information transformed into knowledge mainly on the regions where the ligands were located, specially within the active site of serine protease Factor X and its relationship between the inhibitory activities drawn from the literature. Then we studied a family of coumarin compounds, for which information of their activities was available, building their complexes using molecular docking and graphical display analysis. Based on the fact that one of these compounds is in regular use as anticoagulant, namely warfarin, a coumarin, which has certain advantages as its low cost and high solubility, and disadvantages due to the fact that its action is not specific, we decided to examine analogues of coumarin as inhibitors of Factor X. In the third part of the study a series of coumarins, for which there was no data on their complex formation with Factor X nor on their activity, were studied. The results of the docking studies between Factor X and the coumarin analogues were thoroughly analyzed based on the knowledge acquired in the first and second parts of this work, this allows us to suggest a compound that fits all the characteristics of a good Factor X inhibitor.
The main aim of this work was to seek inhibitors of Factor X, the common factor of the cascade of blood coagulation. The first step was to gain enough insight in the understanding of the crystallographic complexes between the X-factor and small molecules. After extensive analysis of the complexes obtained from databases, using molecular visualization, data, namely the interactions of the ligands and their crystallographic pose, were organized and the information transformed into knowledge mainly on the regions where the ligands were located, specially within the active site of serine protease Factor X and its relationship between the inhibitory activities drawn from the literature. Then we studied a family of coumarin compounds, for which information of their activities was available, building their complexes using molecular docking and graphical display analysis. Based on the fact that one of these compounds is in regular use as anticoagulant, namely warfarin, a coumarin, which has certain advantages as its low cost and high solubility, and disadvantages due to the fact that its action is not specific, we decided to examine analogues of coumarin as inhibitors of Factor X. In the third part of the study a series of coumarins, for which there was no data on their complex formation with Factor X nor on their activity, were studied. The results of the docking studies between Factor X and the coumarin analogues were thoroughly analyzed based on the knowledge acquired in the first and second parts of this work, this allows us to suggest a compound that fits all the characteristics of a good Factor X inhibitor.
Descrição
Palavras-chave
Doking, Data mining, Fator X, Varfarina, Anticoagulantes, Anticoagulants